Chronic obstructive pulmonary disease (COPD) is highly prevalent among U.S. Veterans and is a significant source of morbidity and mortality. Patients with COPD frequently have reduced exercise capacity (defined as a patient's maximal capacity to perform work) and levels of physical activity (a term frequently used to describe a patient's typical daily level of activity). Reduced exercise capacity and physical activity are correlated with significant clinical outcomes, such as disability, all-cause mortality, and healthcare utilization rates. Importantly, exercise capacity and physical activity represent potentially modifiable risk factors in COPD. Exercise training, which is typically performed in the setting of a structured pulmonary rehabilitation program, is currently endorsed by the Global Initiative for Obstructive Lung Diseases (GOLD) guidelines as an essential component of the non-pharmacological management of COPD and has been shown to improve symptoms and health-related quality of life while reducing healthcare utilization. In addition to formal pulmonary rehabilitation, novel programs which focus on improving daily physical activity may provide similar benefits. In addition to the disease-specific benefits above, exercise training and increased physical activity have also been associated with systemic changes such as improved macronutrient metabolism, increased muscle mass, and decreased systemic inflammation. However, COPD patients vary widely in their responses to exercise interventions. Our understanding of the mechanisms which determine exercise capacity and the response to training is incomplete; our hypothesis is that epigenetic mechanisms such as DNA methylation are associated with both baseline exercise capacity and the systemic reprogramming that occurs with training. We propose to examine genome-wide DNA methylation patterns in blood from 2 existing VA-Boston based cohorts of COPD subjects with detailed, objective data on both exercise capacity and daily physical activity. Analysis of the first cohort, a cross-sectional cohort which includes subjects with a broad range of functional limitation, will help to establish the epigenetic determinants of baseline exercise capacity and physical activity (Objective 1). In the second cohort, we will determine longitudinal changes in methylation following an intervention to increase daily physical activity using paired samples collected before and after participation in the Every Step Counts trial (Objective 2). Finally, because traditional pulmonary rehabilitation programs typically involve higher intensity training than programs which target daily physical activity (such as the Every Step Counts program), we propose to collect de novo samples from COPD subjects referred to the VA Boston Pulmonary Rehabilitation program to characterize changes associated with higher intensity training (Objective 3). In addition to providing mechanistic insights on the benefits of exercise and increased physical activity, our proposal has the potential to assist in the development of algorithms for risk stratification and personalized treatment programs for COPD patients.